Abstract
Abstract : Overcoming tumor resistance to platinum chemotherapy is critical for prolonging life in women with advanced ovarian cancer. The nuclear factor-kappaB (NF- B) signaling pathway is a key mediator of tumorigenesis by linking inflammatory pathways to cancer. Inhibitors of NF- B such as thymoquinone (TQ) potentiate the effects of cytotoxic agents, including cisplatin, in ovarian cancer cells. Equally relevant are the potential effects of NF- B inhibition in host cells such as peritoneal macrophages, thought to play pro-tumor (M2-like) or anti-tumor (M1-like) roles during ovarian cancer progression. We will define patterns of NF- B activity in host cells using NF- B reporter (NGL) transgenic mice injected with mouse ID8 ovarian cancer cells. NF- B activity in tumor cells will be monitored through stable transfection of the NGL reporter. We have detected increased NF- B reporter activity in tumor cells and in host macrophages, and increased markers of M2 macrophages in ascites fluid, in late stages of progression. Reducing NF- B activity in tumor cells with TQ treatment was associated with a shift towards M1 macrophages, while longer-term TQ treatment lead to increased ascites, elevated NF- B signaling and an M2 shift. Combined TQ and cisplatin treatment lead to synergistic anti-tumor effects in vitro, reduced tumor burden and apoptotic marks in tumors to a greater extent than treatment with cisplatin alone, and reduced M2, and induced M1, macrophage markers.
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